Structure-Activity Relationships for Osteolathyrism. I. Effects of Altering the Semicarbazide Structure

Schultz, T.W.; Ranney, T.S.; Riggin, G.W.; Cajina-Quezada, M.

doi:10.2307/3226453

Cited by 29 publications

(10 citation statements)

References 17 publications

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“…Summarizing the significance of reactivity indices incorporated in the QSARs, one can see that the stereoelectronic interactions were assisted (or log ( L C~" ) decreases) by the increase in electron acceptor capacities of carbonyl oxygen or sulfur (see the negative correlations of log ( L C~~) with SSN and S,23sN in and (33)*), as well as the positive correlation with Eqns (21,(31,(3,(7), (13), (141, (1% (211, (32) (20) and (34). In other words, during the stereoelectronic interaction, charge is likely to be transferred from the active site of lysyl oxidase to the C=O or C = S group of the toxicants.…”

Section: Discussionmentioning

confidence: 99%

‘Dynamic’ QSAR For Semicarbazide-induced Mortality in Frog Embryos

et al. 1996

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The conventional quantitative–structure–activity relationship (QSAR) provides only a single three‐dimensional (3D) model for a given two‐dimensional (2D) item in the modeling process. However, in complex reaction environments with solvents of different polarity, especially biological systems, the molecules can take the form of different conformers depending on the particular interaction. Therefore, chemical behavior, e.g. toxicity, may be considered the integral effect of a set of conformers rather than the property of a single 3D isomer. The ‘dynamic’ QSAR method is unique in that it provided for the calculation of a set of conformers for 2D representation of each chemical of the series under investigation. Moreover, these conformers can be selected interactively according to the hypothesized mechanism of toxic action. The acute lethality of 36 semicarbazides and thiosemicarbazides, evaluated using the Frog Embryo Teratogenesis Assay: Xenopus (FETAX), was modeled by using the ‘dynamic’ QSAR method. The assumed mode of action, osteolathyrism, was defined by the failure of connective tissue to polymerize properly due to interference with lysyl oxidase. Conformer screenings were based on parameter distribution according to the frontier orbital energies and volume polarizability, conditioning their reactivity and hydrophobicity, respectively. The best results were obtained by the selection of conformers providing prevailing values of electron acceptor properties. Moreover, the best two‐parameter QSARs encompassing all the evaluated compounds incorporate a geometric parameter, the geometric analog of the Wiener topological index, and the local electronic characteristics of the C==O or C==S group, superdelocalizabilities and charges.

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Section: Discussionmentioning

confidence: 99%

‘Dynamic’ QSAR For Semicarbazide-induced Mortality in Frog Embryos

et al. 1996

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“…Semicarbizide has a TI value of 3000, indicating the higher end of this scale. 34 For this study, the mean MAS TI was used as one criterion to assess teratogenic hazard in an effort to increase the predictive accuracy of this measure and to reduce false-positive values. However, FETAX is ordinarily performed by only a single laboratory.…”

Section: Predictive Ability Of the Teratogenic Indexmentioning

confidence: 99%

Phase III interlaboratory study of FETAX part 3. FETAX validation using 12 compounds with and without an exogenous metabolic activation system

et al. 1999

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FETAX (Frog Embryo Teratogenesis Assay—Xenopus) is a 96‐h whole‐embryo developmental toxicity screening assay that can be used in ecotoxicology and in detecting mammalian developmental toxicants when an in vitro metabolic activation system is employed. A standardized American Society for Testing and Materials (ASTM) guide for the conduct of FETAX has been published, along with a companion atlas that helps in embryo staging and in identifying malformations. As part of the ASTM process, an interlaboratory validation study was undertaken to evaluate the repeatability and reliability of FETAX and to evaluate the potential teratogenic hazard of 12 compounds. Three different laboratories participated in the study. All three participating laboratories had extensive experience with the assay. FETAX intralaboratory and interlaboratory variability, as judged by coefficients of variation, were very low. Potential teratogenic hazard was evaluated using two major criteria from FETAX experiments employing metabolic activation systems (MAS). These were the teratogenic index TI (TI = 96‐h lc50/96‐h ec50 (malformation)) and the minimum concentration that inhibits growth (MCIG). A compound was considered teratogenic by this criterion when the MCIG was significantly different from controls at concentrations below the 30% level of the MAS 96‐h lc50. Based on the results of this and other studies, a decision table was constructed in order to evaluate additional studies. Severity of malformations caused, especially near the MAS 96‐h ec50 (malformation), were also evaluated. Four compounds were non‐teratogenic but two compounds were clearly teratogenic. The remaining six compounds were ranked as equivocal teratogens. The results were discussed in light of the difficulty of producing an adequate decision table. FETAX proved to yield repeatable and reliable data as long as care was taken during range‐finding and technicians were adequately trained. The MAS was essential in using FETAX to predict developmental hazard in mammals, and still requires further development. Copyright © 1999 John Wiley & Sons, Ltd.

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“…Of these materials, E showed the least hazard. The use of FETAX in structure-activity relationship (SAR) studies has been well documented [18][19][20][21][22]. Most of the test materials used in the study produced similar malformations in Xenopus and the rat.…”

Section: Discussionmentioning

confidence: 99%